Efficient direct asymmetric aldol reactions in water using chiral diamide as organocatalysts

Abstract

Two chiral diamide organocatalysts, N,N'-(oxybis(4,1-phenylene))bis(pyrrolidine-2- carboxamide) (IVa) and N,N'-(methylenebis(4,1-phenylene))bis(pyrrolidine-2-carboxamide) (IVb), were developed to catalyze asymmetric aldol reactions in water with low catalyst loadings ranging from 30% to 10%. This study aimed to evaluate the influence of chiral concavity of oxygen bridge catalyst IVa on the transition state of aldol reaction in water compared to methylene bridge catalyst IVb in terms of diastereoselectivity, optical purity, reaction time and catalyst loading. The reaction conditions were optimized using p-nitrobenzaldehyde as acceptor and cyclohexanone as donor in the aldol reaction. Oxygen-bridged catalyst IVa showed superior performance to catalyst IVb in water, achieving a reaction time of 28 h, a diastereoselectivity ratio of 78:22 (anti/syn), and an enantiomeric excess of up to 97%. This effect was attributed to the assembly of a chiral cavity facilitated by hydrogen bonds at the oil– water interface and the proximity of the catalytic sites favored by the oxygen bridge of catalyst IVa. Organic solvents, such as DMSO, DCM, and hexane, offered excellent diastereoselectivity, but had reaction times four times longer than those in water. This study highlights the potential of organocatalyst IVa for environmentally friendly asymmetric aldol reactions.